Protein Degradation in Health and Disease

Volume 29 of the series Progress in Molecular and Subcellular Biology pp 1-15

Roles of SCF and VHL Ubiquitin Ligases in Regulation of Cell Growth

  • Takumi KamuraAffiliated withDepartment of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University
  • , Joan W. ConawayAffiliated withProgram in Molecular and Cell Biology, Oklahoma Medical Research FoundationHoward Hughes Medical Institute, Oklahoma Medical Research FoundationDepartment of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City
  • , Ronald C. ConawayAffiliated withProgram in Molecular and Cell Biology, Oklahoma Medical Research Foundation

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Over the past few years, a growing body of evidence has brought to light critical roles for ubiquitin-dependent protein degradation in controlling the cellular levels of a large variety of proteins such as cyclins, cyclin-dependent kinase inhibitors, oncogenes, and tumor suppressors, which play integral roles in regulation of cell growth. Ubiquitin-dependent protein degradation is a complex, multistep process that proceeds with the tagging of target proteins with a poly-ubiquitin chain and culminates with the processive, ubiquitin- dependent degradation of tagged proteins by the 26S proteasome (Hershko et al. 1983; Hochstrasser 1995, 1996; Hershko and Ciechanover 1998). In the first step, the C-terminus of ubiquitin is covalently linked through a thioester bond to the active site cysteine residue of an El ubiquitin-activating enzyme. Ubiquitin is then transferred from the El via a thioester linkage to an active site cysteine residue in one of a number of E2 ubiquitin-conjugating enzymes. Ubiquitin is then either (1) conjugated directly via an isopeptide bond to the 8-amino group of a lysine in the target protein, (2) conjugated via an isopeptide bond to another ubiquitin moiety on the target protein as part of synthesis of the poly-ubiquitin tag, or (3) transferred from the E2 via a thioester bond to an active site cysteine residue in one of a growing family of E3 ubiquitin ligases, which then conjugate ubiquitin to specific target proteins.